In patients with IDDM, short-term co-therapy with subcutaneous (SC) rhIGF-I and insulin improves glycemic control, reduces insulin requirements and normalizes parameters of the somatotropin axis. The present study was undertaken to assess the effects of longer-term, multidose rhIGF-I treatment in 224 patients with IDDM (ages 11-66 yrs.). During this 16 week study (2 wks pretreatment, 12 wks treatment, 2 wks follow-up), pts. were randomized in a double-blind fashion to receive twice daily SQ injections of insulin and placebo (n=53), or insulin and rhIGF-I at an rhIGF-I dose of: a) 80:60 (5g/kg am:pm, n=56); b) 80:40 (n=57); or c) 40:40 (n=54). Home blood glucose (BG) monitoring was performed 4 times daily and in all groups pts. were instructed to adjust concurrent insulin doses to optimize BG levels (i.e., toward DCCT target BGs). All groups were comparable with respect to pt. demographics, HgbA1c and fasting BG prior to treatment. Co-therapy with rhIGF- I/insulin for 12 weeks reduced baseline HgbA1c values by 1.2% (40:40), 0.9% (80:40) and 1.0% (80:60), compared with intensified insulin therapy alone (0.6%). Preliminary data for the rhIGF-I 40:40 dose group is shown below compared with placebo (mean + SEM). (* = p < .01 for Baseline vs. Week 12; # = p < 0.01 for pairwise week 12 comparisons, Insulin/Placebo vs. Insulin/rhIGF-I) Insulin/Placebo Insulin/rhIGF-I Baseline Week 12 Baseline Week 12 HgbA1c (%) 9.24 + .18 8.65 +.18* 9.21+.17 8.05 + .13*# Insulin Dose(units/d) 53 + 4 59 + 4 52 + 3 42 + 3*# Free IGF-I (ng/ml) 0.2 + 0.1 0.7 + 0.4 0.1 + 0.1 0.8 + 0.2 Body weight did not change significantly in either group. Moreover, despite better glycemic control, reported hypoglycemic events were no more frequent in subjects treated with insulin/rhIGF-I 40:40 (45 episodes) compared with insulin alone (42 episodes, p=0.65). The rhIGF- I 40:40 dose was also well tolerated. Higher rhIGF-I doses were associated with an unacceptable incidence of adverse events such as peripheral edema, jaw pain and optic disc swelling. These results demonstrate that rhIGF-I/insulin co-therapy improves glycemic control in pts. with IDDM, beyond that achievable with intensified insulin management alone, and suggest that longer-term trials are needed to evaluate the safety and efficacy of rhIGF-I as a new therapy for improving metabolic control in IDDM. Based upon the results of this study, Genentech Inc. is now initiating a year-long, multicenter, multidose study of the combined effects of Insulin and rhIGF-I on glycemic control in IDDM. This study will enroll approximately 1400 patients nationally, at about 100 health care facilities.